Process for the preparation of iopamidol

ABSTRACT

The present invention discloses a process for the preparation of Iopamidol of formula (II) 
     
       
         
         
             
             
         
       
     
     and comprising the following steps:
         a) reacting the Compound (I) wherein X is OR 2  or R 3 , and wherein R 2  and R 3  are a C 1 -C 6  linear or branched alkyl, C 3 -C 6  cycloalkyl, C 6  aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I);   b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N-(S)-2-(acetyloxy)propanoyl derivative of Compound (II);   c) alkaline hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b).       

     The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.

The present invention relates to the field of organic chemistry, inparticular to the synthesis of iodinated contrast agents, more inparticular to the use of boron oxyacids and derivatives thereof asprotecting groups. The present invention provides also compounds usefulas intermediates in the above synthesis.

BACKGROUND OF THE INVENTION

Contrast agents, or contrast media, are substances that can alter theway in which a region is analyzed in medical imaging. In particular,they are able to change the contrast of an organ, an injury, or anyother surrounding structure, to make visible such details that otherwisewould be difficult to detect or appreciate.

Contrast agents are primarily used in the radiological or in the nuclearmagnetic resonance diagnostic fields. Depending on the field ofapplication, these derivatives present structural features, such as, inthe case of molecules useful as contrast agents for X-rays analysis, thepresence of one or more atom with high atomic number (e.g. iodine orbarium).

Iopamidol(N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide)(II), whose structural formula is indicated below, is one of thenumerous tri-iodinated diagnostic agents, commercially available andwidely used for this purpose:

The widespread use of this compound in diagnostics makes necessary forthe manufacturers to dispose of easy and convenient syntheses on anindustrial scale. Iopamidol and its synthesis were first disclosed inGB1472050.

Several synthetic approaches have been since then described: they aremostly characterised by the conversion of aromatic amino derivativesinto the corresponding carboxamides, by reaction with a suitableα-hydroxyacid derivative, see for instance: WO 02/44132, WO02/44125, WO96/37459, WO 96/37460, U.S. Pat. No. 5,362,905, WO 97/47590, WO98/24757, WO 98/28259 and WO 99/58494.

5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide (V) is a key intermediate in the synthesis of Iopamidol. Asshown in Scheme 1 below where prior art synthesis has been summarized,its iodination gives the intermediate5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide(IV) which may be further reacted with suitable acylating agents, suchas acetic anhydride in order to protect the hydroxyl groups (asdescribed, i.e. in WO 02/44132 or in WO00/050385) and prevent theirreaction with N-(S)-2-(acetyloxy)propanoyl chloride(2-acetyloxypropanoyl chloride) in the subsequent reaction. Byacetylating the more reactive carboxamido-hydroxy groups, the use of anexcess of 2-acetyloxypropanoyl chloride is avoided. However, theprotective group, after the final deprotection with NaOH, is lost andcannot be recycled.

Furthermore, in order to protect the hydroxyl groups, an excess ofacetic anhydride is required and its presence in the mixture isincompatible in the next reaction step. Subsequently, additionalprecipitation and crystallization steps are required.

The main drawback of this approach is related to the isolation of theintermediate (VI), to obtain the solid in a suitable crystalline form.This procedure may lead to a loss of 10% in the yield.

There is the need of an economical synthesis of Iopamidol, in particulara synthesis allowing the recovery and recycle of the reactant used ashydroxyl protective group.

There is also the need to provide a synthesis, which, at least in thelast steps, allows a one-pot series of reactions in order to avoid theisolation of intermediate compounds and to increase the overall yield.

Furthermore, reactants recovery, together with a decreased wasteproduction and disposal represent highly desirable tasks in view of apositive final reaction balance.

Boron derivatives are known as protective agents in chemical synthesis.

GB2331098 and H R Bjørsvik, H Priebe, J Cervenka, A W Aabye, TGulbrandsen and A C Bryde (A Selective Process for N-Alkylation inCompetition with O-Alkylation: Boric Acid, Borax, and Metaborate as aCheap and Effective Protecting Group Applicable for Industrial-ScaleSynthetic Processes; Organic Process Research and Development 2001, 5,472-478) disclose a process for N-alkylation of compounds containing 1,2and/or 1,3 diol structures. Iodinated contrast agents are disclosed asparticular embodiment. In order to avoid competing O-alkylation, thisdocument teaches the use of boron oxyacid as diol protecting agents.Salts and esters can also be used. The reaction involving diolprotection by the boron oxyacid is carried out in water. After theN-alkylation reaction has come to accomplishment, diol deprotection iscarried out.

Another different use of boric oxyacids in connection with iodinatedcontrast media is disclosed in Journal of Hazardous Materials 205-206(2012) 10-16 (I Rustighia, I Donatia, M Ferluga, C Campa, A E Pasqua, MRossi, S Paoletti; Borate complexes of X-ray iodinated contrast agents:Characterization and sorption studies for their removal from aqueousmedia). The Authors show an effective use of boric oxyacids as a meansfor removing iodinated contrast media from wastewater. This adduct has agood stability at alkaline pH and is adsorbed on the ionic resin Dowex1X4, from which it is desorbed by means of a number of desorbing agents,mainly salts.

SUMMARY OF THE INVENTION

It has now been found boron-containing protective groups which areversatile and efficiently recyclable. The new protectingboron-containing functions enable a one-pot synthesis, withoutintermediate isolation, allowing recovery and recycling of theprotective functions and a significant increase in the overall processyields.

Moreover, these protecting groups can be recovered and recycled in theprocess and this represents a significant advantage in terms ofcost-effectiveness of the entire process and environmental awareness.

It is an object of the present invention an intermediate Compound offormula (I)

wherein X is OR₂ or R₃, and wherein R₂ and R₃ are a C₁-C₆ linear orbranched alkyl, C₃-C₆ cycloalkyl, C₆ aryl, optionally substituted with agroup selected from the group consisting of methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, t-butyl and phenyl.

It is another object of the present invention a process for thepreparation of Iopamidol of formula (II)

comprising the following reaction summarized in Scheme 2:

wherein the different groups are as above defined and comprising thefollowing steps:

-   -   a) reacting the Compound (I) with the acylating agent        (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to        provide the N-(S)-2-(acetyloxy)propanoyl derivative of Compound        (I);    -   b) hydrolyzing the intermediate from step a) with an aqueous        solution at a pH comprised from 0 to 7, preferably from 6 to 7        by adding water or a diluted alkaline solution such as sodium        hydroxide or potassium hydroxide, freeing the hydroxyls from the        boron-containing protective groups, obtaining the acetyloxy        derivative of Compound (II) and optionally recovering the boron        derivative;    -   c) alkaline hydrolysis of the acetyloxy derivative of        Compound (II) restoring the (S)-2-(hydroxy)propanoyl group to        obtain Iopamidol (II).

In a first preferred embodiment, in the compound of formula (I), X isOR₂, wherein R₂ is as above defined and preferably selected from thegroup consisting of: ethyl, n-propyl and n-butyl.

In a second preferred embodiment, in the Compound of formula (I), X isR₃, wherein R₃ is as above defined and preferably selected from thegroup consisting of: butyl, isobutyl, isopentyl, n-pentyl, n-hexyl,ciclopentyl, ciclohexyl or phenyl, optionally substituted with methyl,ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl or phenyl.

In step a) of the above process, said reaction medium is an organicsolvent, selected from the group consisting of N,N-dimethylformamide,N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide,N-methylpyrrolidone, N-ethylpyrrolidone, tetramethylurea,N,N′-dimethylethyleneurea (DMEU), N,N′-dimethylpropyleneurea (DMPU),optionally in admixture with a water-immiscible organic solvent, hereindefined co-solvent.

The acylating agent employed in step (a) of the process enables for theformation of the proper carboxamide that, upon deprotection of thehydroxyl group in the subsequent step (c) of the process, provides forthe corresponding [(2S)(2-hydroxy-1-oxopropyl)amino] moiety beingpresent in the chemical structure of Iopamidol.

From all of the above it is thus apparent to the skilled person thatacylating agents alternative to (S)-2-(acetyloxy)propanoyl chloride maybe also employed according to the process of the invention.

As an example, acylating agents alternative to(S)-2-(acetyloxy)propanoyl chloride may thus comprise any of thecorresponding compounds bearing a leaving group suitable for carboxamidoformation other than chlorine, and/or any suitable hydroxyl protectinggroup other than acetyl to be then cleaved according to step (c) of theprocess.

In step b) after the hydrolysis of the boron protective groups, recoveryof the boron-derivative can be carried out by chromatography or bysolvent extraction. In case chromatography is used, a suitable resinspecific for boron removal can be used. For example, a suitable resincontains diolic groups and is designed to boric or boronic acidcomplexation and subsequent sequestration. A preferred resin is the onecontaining N-methyl (polyhydroxyhexyl)amine functional groups alsocalled methylglucamine. A commercially available example of such a resinis Amberlite® IRA743. However, other resins can be selected among thecommercially available ones, for example or equivalent or analoguecolumns, such as Duolite ES-371, Diaion CRB 02, Dowex BSR 1, Purolite S108 and Purolite S110. Further details are provided in the DetailedDescription below. Hydrolysis of boron-containing protecting groups ismade by water addition.

However, recovery of the boron-derivatives is preferably carried out bysolvent extraction, in particular when, according to Scheme 3 andreactant 3, R₃ is butyl, phenyl or a methyl substituted phenyl (tolylgroup), butyl or when a boroxine of Formula III is used and R₃ has thesame meaning as for reactant 3.

Overall, the process for the preparation of Iopamidol according to thepresent invention is presented in the following Scheme 3:

In Scheme 3, which describes the synthesis of Iopamidol (II) from5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide(IV), X is as defined above and in the first reaction step, the numbers1; 2; 3, represent reactants in single, alternative embodiments. Notshown in the scheme, but part of the present invention is also thealternative reactant boroxine of Formula III.

According to the present invention, the terms “boron derivative”, “boronderivatives” or “boron-containing protective group” mean the boroncompounds which are used according to Scheme 3 above, with the startingCompound (IV) to give the Compound (I); as well as the compoundsproduced in the hydrolysis of the intermediate (I) and subsequentfreeing the hydroxyls from the boron-containing protective groups. Theseboron derivatives can be optionally recovered in the above step c) andrecycled in the process. The terms “boron derivative” or “boronderivatives” generally comprise boron oxyacids (such as boric acid andboronic acids), esters thereof and boroxine.

According to a first preferred embodiment of the present invention, andreferring to Scheme 3, the intermediate Compound (I), wherein X is OR₂,is obtained by reacting Compound (IV) with one of a boric acid in anR₂OH alcohol or a borate ester B(OR₂)₃, wherein R₂ is as above defined.

According to a second preferred embodiment of the present invention, andalso referring to Scheme 3, the intermediate Compound (I), wherein X isR₃ is obtained by reacting the Compound (IV) with a boronic acidR₃—B(OH)₂, wherein R₃ is as above defined. Alternatively, this secondpreferred embodiment, not shown in Scheme 3, but part of the presentinvention is achieved by reacting the Compound (IV) with a boroxine offormula (III):

wherein R₃ is as above defined.

In one embodiment of the present invention, said process for thepreparation of Iopamidol (II) comprises:

x) reacting the Compound of formula (IV) with a boric acid esterB(OR₂)₃, wherein R₂ is as above defined (see Scheme 3 above, reactant 2)to provide the intermediate of formula (I) above disclosed;

a) treating said intermediate Compound (I) with(S)-2-(acetyloxy)propanoyl chloride to obtainN-(S)-2-(acetyloxy)propanoyl derivative of Compound (I)

b) releasing boric acid; and

c) restoring the (S)-2-(hydroxy)propanoyl group to obtain Iopamidol (II)by alkaline hydrolysis. In said process, the boric acid ester can berestored for subsequent use. In this connection, the boric acid,obtained in the final step, is recovered, reacted with an R₂—OH alcohol,wherein R₂ is as above defined, and recycled in a new process.

In an embodiment of the recovery step, said boric acid is treated with asuitable resin, such as a resin specific for boric acid, for example thecommercially available Amberlite™ IRA743, being intended that the personskilled in the art can select the proper way to recover boric acid byresorting to the general common knowledge in this matter.

In another embodiment of the present invention, said process for thepreparation of Iopamidol (II) comprises:

x′) reacting the Compound (IV) with boric acid with an alcohol R₂OH,wherein R₂ is as above defined (see Scheme 3 above, reactant 1) toprovide the intermediate of formula (I) above disclosed;

a) treating said intermediate (I) with (S)-2-(acetyloxy)propanoylchloride to obtain N-(S)-2-(acetyloxy)propanoyl derivative of Compound(I),

b) releasing boric acid; and

c) restoring the (S)-2-(hydroxy)propanoyl group to obtain Iopamidol (II)by alkaline hydrolysis.

In said process, the boric acid and the alcohol form the correspondingboric acid ester in situ, and the process can be carried out as in thecase explained above using the boric acid ester. The boric acid ester isthen restored for subsequent use as shown above.

The process can be carried out in batch mode, or, conveniently, incontinuous mode.

In another embodiment of the present invention, in the Compound offormula (I) X is R₃, as above defined and is preferably a phenyl, amethyl substituted phenyl, a methyl or a butyl group.

According to this embodiment, an exemplary process for the preparationof Iopamidol (II) is illustrated in the above Scheme 3, reactant 3.

Said process comprises:

x″) reacting the Compound of formula (IV) with a boronic acid R₃—B(OH)₂or a boroxine (III) wherein R₃ is as above defined, and is preferablyselected from a phenyl, a methyl substituted phenyl, methyl and butyl toprovide the intermediate of formula (I);

a) treating said intermediate (I) with (S)-2-(acetyloxy)propanoylchloride to obtain the acetyloxy derivative of Compound (I),

b) releasing boronic acid;

c) restoring the (S)-2-(hydroxy)propanoyl group to obtain Iopamidol (II)by alkaline hydrolysis.

In said process the boronic acid can be recovered for subsequent use. Inthis connection, the boronic acid, obtained in the final step, isrecovered with two possible approaches: by extracting with an organicwater-immiscible solvent, for example 4-methyl-2-pentanone, 2-pentanone,3-pentanone, dibutyl ether, 2-methyl-tetrahydrofurane, ciclopentylmethylether, methyl isopropyl ketone, methyl isopentyl ketone, ethyl acetate,butyl acetate, pentyl acetate, isopentyl acetate, isopropyl acetate,removing the solvent and recycling the recovered boronic acid in theprocess, or alternatively, as described above for boric or boronic acidcomplexation, i.e. by treating the final reaction mixture with a resinsuitable for boron removal, such as those mentioned in step c) above,among which, for example, an Amberlite® IRA 743.

The recovery process can be carried out in a batch mode, or, moreconveniently, in a continuous mode. In a preferred embodiment,phenylboronic, p-tolyl boronic or n-butylboronic acids are used andrecycled.

In another embodiment, in the Compound of formula (I), X is R₃, as abovedefined, preferably phenyl, a methyl substituted phenyl, methyl orbutyl. More preferably in Compound of formula (I) R₃ is phenyl. Thepreparation of compound of formula (I) as an intermediate in thepreparation of Iopamidol (II) can also be carried out as disclosed inthe previous embodiment, but using a boroxine of formula (III) is usedinstead of the boronic acid. Triphenylboroxine and trimethylboroxine arepreferred boroxines and R₃ in compound (I) is preferably phenyl ormethyl. According to this embodiment, phenylboronic acid ormethylboronic acid are released upon hydrolysis of the hydroxyl groups,freed from the boron-containing protective moiety and the boronic acidscan be restored for subsequent use, as disclosed above.

Compound (I) can be isolated and characterized as will be described morein details below. Accordingly, compound of formula (I) represents afurther object of the present invention as well as its use asintermediate in the synthesis of Iopamidol (II).

After the OH protection is completed, which is preferably achieved bywater distillation, an acetylation step is carried out on Compound (I)preferably in a solvent selected from the group consisting of:N,N-dimethylformamide, N,N-dimethylacetamide (DMAC),N,N-diethylacetamide, N,N-dimethylpropionamide, 1-methyl-2-pyrrolidone,1-ethyl-2-pyrrolidone, tetramethylurea, N,N′-dimethylethyleneurea(DMEU), N,N′-dimethylpropyleneurea (DMPU). PreferablyN,N-dimethylacetamide is used and more preferably, N,N-dimethylacetamidehas a very low water content or is anhydrous. The solvent may alsocomprise a co-solvent which is an organic solvent immiscibile in water,selected among: 4-methyl-2-pentanone, 2-pentanone, 3-pentanone, dibutylether, 2-methyl-tetrahydrofurane, ciclopentylmethyl ether, methylisopropyl ketone, methyl isopentyl ketone, ethyl acetate, butyl acetate,pentyl acetate, isopentyl acetate, isopropyl acetate. A preferredsolvent/co-solvent mixture is represented by DMAC and4-methyl-2-pentanone, 3-pentanone or 2-pentanone.

The presence of a co-solvent in step a) is particularly preferred whenthe boron protective groups have to be recovered at a later time byco-solvent extraction.

In another embodiment of the present invention, the process can becarried out starting from a suitable Compound (V).

According to this embodiment, an object of the present invention is aprocess according to the following Scheme 4:

Scheme 4 describes the synthesis of Iopamidol (II) from5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide(V); X is as defined above and in the first reaction step the numbers 1;2; 3 represent reactants in single, alternative embodiments. Not shownin the scheme, but part of the present invention is also the alternativereactant boroxine.

The Compound (V) can also be prepared as described in WO02/44125 orWO00/029372.

The iodination of the aromatic ring is also carried out according tomethods disclosed in the numerous literature on Iopamidol synthesis,e.g. in WO96/037458, WO2009/103666, WO2010/121904, WO2011/154500 andWO2011/003894.

In a particular aspect, and object of the present invention, Compound(V) is prepared according to the following Scheme 5:

Scheme 5 describes the synthesis of5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide(V) from 5-Nitro-isophthalic acid (5-NIPA), wherein:

-   -   i) 5-nitroisophthalic acid is treated with an R₁OH alcohol,        wherein R₁ is a linear or branched C₁-C₄ alkyl, to provide the        corresponding diester (VI);    -   ii) the 5-nitro group is reduced to the corresponding 5-amino        group to Compound (VII);    -   iii) the diester is reacted with 2-amino-1,3-propandiol to        provide Compound (V).

Another object of the present invention is a process for the preparationof Iopamidol according to the following Scheme 6:

Scheme 6 describes the synthesis of Iopamidol (II) from5-Nitro-isophthalic acid, wherein:

-   -   i) 5-nitroisophthalic acid is treated with an R₁OH alcohol,        wherein R₁ is a linear or branched C₁-C₄ alkyl, preferably        butyl, to provide the diester (VI);    -   ii) the 5-nitro group is reduced to provide the Compound (VII);    -   iii) the diester is reacted with 2-amino-1,3-propandiol to        provide the Compound (V);    -   iv) the Compound (V) is iodinated at positions 2,4,6, to provide        the Compound (IV);    -   v) the Compound (IV) is treated with boric acid or a derivative        thereof according to the present invention, to provide the        Compound of formula (I) according to the present invention;    -   vi) the Compound of formula (I) is finally transformed into        Iopamidol (II) as described above.

The above objects of the present invention and other embodiments will benow disclosed in detail in the following description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for the preparation ofIopamidol (II) comprising the following reaction:

wherein X is OR₂ or R_(3,) and wherein R₂ and R₃ are a C₁-C₆ linear orbranched alkyl, C₃-C₆ cycloalkyl, C₆ aryl, optionally substituted with agroup selected from the group consisting of methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, more preferablyphenyl, a methyl substituted phenyl, methyl and butyl,

and comprising the following steps:

-   -   a) reacting the Compound (I) with the acylating agent        (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to        provide the N-(S)-2-(acetyloxy)propanoyl derivative of Compound        (I);    -   b) hydrolyzing the intermediate from step a) with an aqueous        solution at a pH comprised from 0 to 7, preferably from 6 to 7        by adding water or a diluted alkaline solution such as sodium        hydroxide or potassium hydroxide, freeing the hydroxyls from the        boron-containing protective groups, obtaining the acetyloxy        derivative of Compound (II) and optional recovery of the boron        derivative;    -   c) alkaline hydrolysis of the acetyloxy derivative of        Compound (II) restoring the (S)-2-(hydroxy)propanoyl group to        obtain Iopamidol (II).

According to step a) the reaction medium is preferably a reaction mediumhaving the minimum water content compatible with the reaction, morepreferably, an anhydrous reaction medium.

The reaction medium is conveniently selected by the person of ordinaryskill in the art, based on the common knowledge for this kind ofreaction. The medium is typically an organic solvent capable ofdissolving the Compound of formula (I) and not interfering with theacylating reagent (S)-2-(acetyloxy)propanoyl chloride. Preferredexamples of organic solvent usable in this step are inert dipolaraprotic solvents, such as for example N,N-dimethylformamide,N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide,1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, tetramethylurea,N,N′-dimethylethyleneurea (DMEU), N,N′-dimethylpropyleneurea (DMPU).N,N-Dimethylacetamide (DMAC), with a low water content or anhydrous, isthe preferred one. The organic solvent used in this step can be also inadmixture with a co-solvent. Preferred co-solvents are selected amongthose organic and immiscible in water, such as: 4-methyl-2-pentanone,2-pentanone, 3-pentanone, dibutyl ether, 2-methyl-tetrahydrofurane,ciclopentylmethyl ether, methyl isopropyl ketone, methyl isopentylketone, ethyl acetate, butyl acetate, pentyl acetate, isopentyl acetate,isopropyl acetate. A preferred solvent/co-solvent mixture is representedby DMAC and 4-methyl-2-pentanone, 3-pentanone or 2-pentanone.

In step a) the stoichiometric ratio between the Compound of formula (I)and the chiral acylating agent (S)-2-(acetyloxy)propanoyl chloride isthe one usually employed in the synthesis of Iopamidol (see for exampleGB1472050 Example 1b). A stoichiometric excess is preferred depending onthe reaction conditions.

Humidity should be kept controlled in the reaction environment,therefore, it is preferred to carry out the reaction in an inertatmosphere, for example dry nitrogen or argon.

The reaction temperature is typically around room temperature, eventhough higher or lower temperatures can be used compatibly with thestability of the reactants and the final product. The reaction iscarried out for a time spanning from few minutes to few days, typicallyfrom 8 to 30 hours, more conveniently from 12 to 30 hours, for examplefor 18 hours. Reaction time depends on the reaction conditions: thesolvent used, reactants ratio and purity, temperature. The person ofordinary skill in the art can find the optimal conditions by recurringto his personal knowledge and experience. As formerly reported it isapparent to the skilled person that acylating agents alternative to(S)-2-(acetyloxy)propanoyl chloride may be also employed according tothe process of the invention.

Among them are, as an example, the compounds of formula (VIII) below

wherein Z represents a suitable leaving group among those conventionallyknown for the acylation reactions leading to carboxamido derivatives andCOW represents any suitable hydroxyl protecting group to be then cleavedaccording to step (c) of the process.

Conventional examples of leaving groups Z may for instance comprisebromine and iodine atoms or —COZ may represent any suitable ester oranhydride group, including the derivatives of sulfuric or sulfonic acid.

Suitable esters or anhydrides may thus include the compounds of formula(VIII) wherein Z represents a straight or branched C₁-C₆ alkoxy group,or an aryloxy or arylalkoxy group wherein aryl may for instancerepresent phenyl or optionally substituted phenyl, or even any suitableheterocyclyloxy group.

Additional esters or anhydrides may also comprise, as an example, thecompounds of formula (VIII) wherein Z represents an optionallysubstituted group selected from alkylsulfonyloxy, arylsulfonyloxy,alkylarylsulfonyloxy, straight or branched C₁-C₆ acyloxy, arylcarboxy,arylalkylcarboxy, and the like.

Specific examples of Z groups alternative to chlorine may thus includebromine, iodine, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy,isobutyloxy, sec-butyloxy, tert-butyloxy, phenoxy, benzylozy,succinimidyloxy, mesylate, tosylate, brosylate, acetoxy, propanoyl,benzoyl, and the like.

In addition, further examples of Z groups alternative to chlorine may bealso represented by known phosphorous containing leaving groups such as,for example, phosphonates.

Alternatively, the acylation reaction in step (a) of the process couldbe even carried out in the presence of the corresponding carboxylic acidderivative wherein Z stands for hydroxy. Said reaction is widely knownin the art and can be achieved by reacting the acid and the aminoderivative in the presence of suitable coupling agents among which are,for instance, dicyclohexylcarbodiimide or N,N′-carbonyldiimidazole.

As far as the group COW is concerned, we refer to any suitable hydroxylprotecting group to be then cleaved in step (c) of the process so as torestore the hydroxyl function.

Typical hydroxyl protecting groups may thus comprise ester derivativeswherein W represents an alkyl, for instance a straight or branched C₁-C₆alkyl, optionally substituted by one or more halogen atoms, or an arylor arylalkyl group. Suitable aryl groups may thus comprise phenyl orphenyl groups optionally substituted by one or more halogen atoms ornitro groups.

The operative conditions to be employed in step (a) whilst carrying outthe acylation reaction with any acylating agent alternative to(S)-2-(acetyloxy)propanoyl chloride are those presently reported oranyhow known in the art or easily derivable by the skilled person.Likewise, the subsequent cleavage of the selected hydroxyl protectinggroup, according to step (c) of the process, is known to be accomplishedaccording to conventional techniques and operative conditions widelyreported in the art or anyhow easily derivable by the skilled person.

The above compounds of formula (VIII) are known or can be easilyprepared according to known methods.

The completion of the reaction can be detected by ordinary analyticalmeans used in organic chemistry, for example spectrometric equipment,such as ¹H-NMR, IR; chromatographic equipment, for example TLC, HPLC,GLC.

To this purpose, and with reference to Scheme 2, the reaction mixtureresulting from step a) of the process of the present invention istransferred into an aqueous medium (step b). Conveniently, water (or adiluted alkaline solution, such as a NaOH or a KOH solution) is added inthe same reaction vessel where acylation step a) has been performed.Transfer of the organic phase into a different vessel containing watercan also be done. Normally, the amount of water volume or weight is atleast the same of the organic phase, preferably higher, for example 2-3times the volume of the organic phase, compatibly with the subsequentoperations and not exceeding in dilution. Acetyl Iopamidol protectedhydroxyl groups are then freed from the boron-containing protectinggroups by hydrolysis, adding water or diluted alkaline solutions, suchas diluted NaOH or KOH to the acidic reaction mixture. The recovery ofthe boron-containing protective groups after their hydrolysis on theacetyloxy derivative of Compound of Formula (I) in step b) can beperformed by treating the reaction mixture with an ion exchange resin,typically an anionic exchange one, preferably one specific for boronsequestration, such as a resin with diolic functions, more preferablywith functions selected in the group consisting of: methylglucamine,diethanolaminomethyl preferably on a polystyrene matrix, glycidylpreferably on a methacrylate matrix, iminodipropylene glycol,amino-bis(propane cis 2,3 diol), hydroxyethylamino propylene glycol.Some resins, such as those with methylglucamine functions are alsocommercially available and can be selected from manufacturers'catalogues, for example Resindion of Mitsubishi Chemical, Dow Chemical,etc. Typical example is Duolite ES-371, preferred example is Amberlite™IRA743 by Dow Chemical Company or other suppliers. This embodimentapplies preferably to boric acid derivatives: conveniently, the resin isloaded into a column and the phase is eluted through it.

Alternatively and according to the preferred embodiment described belowwhen a boronic acid such as phenylboronic, p-tolylboronic orbutylboronic acid or a boroxine (such as phenylboroxine ormethylboroxine) are used as the boron-containing protective groups, therecovery of boron-containing protective groups is carried out byextraction with an organic solvent immiscible in water selected from thegroup consisting of: 4-methyl-2-pentanone, 3-pentanone, 2-pentanone,dibutyl ether, 2-methyl-tetrahydrofurane, ciclopentylmethyl ether,methyl isopropyl ketone, methyl isopentyl ketone, ethyl acetate, butylacetate, pentyl acetate, isopentyl acetate, isopropyl acetate. Preferredextraction solvents are 4-methyl-2-pentanone (MIBK), 3-pentanone or2-pentanone. According to this embodiment and to Scheme 3, Compound I ispreferably prepared directly in a polar solvent in admixture with thewater-immiscible organic solvent (co-solvent) useful forboron-containing protective groups extraction as described below. Apreferred solvent/co-solvent mixture is represented by DMAC and4-methyl-2-pentanone (MIBK), 3-pentanone or 2-pentanone (i.e. in a ratiocomprised from 1:10 to 1:4 weight/weight).

The boronic acid or boroxine are added in a slight molar excess comparedto the triiodobenzenecarboxamide (Compound IV). The suspension isadmixed and heated to 90-95° C. and water is preferably distilled off tocomplete the protection reaction. Formation of Compound I can beassessed i.e. by ¹H-NMR.

According to a particularly preferred embodiment, steps a)-c) can thenbe carried out in a single pot, for example as follows:(S)-2-(acetyloxy) propanoyl-chloride is added to the mixture undernitrogen atmosphere and stirred for a few hours, to achieve theacetyloxy propanoyl derivative of Compound I. Release of the boronprotecting groups by hydrolysis of the acetyloxy propanoyl derivative ofCompound I is usually obtained with (water or) a diluted alkalinesolution, to neutral pH (i.e. comprised from 5-8), preferably comprisedfrom 6-7 which allows for a good selectivity in the further recovery ofthe boron protective group with the water-immiscible solvent.

The recovery of the boron protective group, which is usuallyquantitative, can be carried out in batch or in a continuous mode. Inboth procedures the amount of organic water immiscible solvent ismaintained in a ratio with the boronic acid compound comprised from 1:10to 1:20, preferably from 1:13 to 1:16 more preferably about 1:15. In thebatch procedure this amount can be added in one or more aliquots.

The so obtained biphasic mixture comprises an aqueous phase with theacetyl-Iopamidol, which is recovered for purification, followed byhydrolysis of the acetyl group to achieve Iopamidol, while the boronicacid is partitioned in the organic phase which is recovered, optionallypreferably distilled to concentrate the boron-protective containinggroups and recycled.

Recycling of the boronic acid solution can be accomplished afteraddition of the reaction solvent of choice, i.e. DMAC (5-10% of theorganic solution) and co-solvent distillation, preferably under vacuumand at a temperature below 40° C. to achieve a boronic acidconcentration of about 10%. The recycled solution can then be usedindefinitely preferably by addition of a small quantity (i.e.corresponding to 5-20% of recycled boronic acid present in the organicsolution) of fresh boronic acid.

As the next step, either the aqueous solution eluted from the columnspecific for sequestering the boronic acid, or alternatively coming fromthe extraction by means of an organic solvent, and comprisingN,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)(2-acetoxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide,also known as acetyl-Iopamidol is then de-salted from organic andinorganic salts by means of ion exchange resins.

In step c) the neutral solution obtained is loaded onto a strong anionicresin, preferably a resin with trimethylamine functional groups bound toa polymeric matrix material such as Relite® 3ASFB, to release rawIopamidol, essentially as described in U.S. Pat. No. 5,550,287 with theexception that Iopamidol is released with a diluted aqueous solution ofa strong acid, such as HCl, H₂SO₄, being hydrochloric acid preferred.Alternatively, Iopamidol release can be effected in batch, in basicconditions, as disclosed e.g. in WO97/30735, Example 1, i.e. by treatingthe acetyl Iopamidol containing mix in strongly alkaline pH conditionsfollowed by salt removal, preferably by chromatography onto ionicexchange resins, preferably at first onto a strongly cationic resinfollowed by a weak anionic resin.

Hydrolysis of acetyl-Iopamidol onto a strong anionic resin, is moreefficient and is therefore preferred. According to this embodiment, theprocess is made simpler because the purification and hydrolysis are, inpractice, carried out in a single step.

The product is further purified in a conventional manner, for example asdescribed in more details in the Experimental Part by crystallizationwith 2-butanol-water to a pharmaceutical grade according to the nationalor European Pharmacopoeias.

The boric acid or the derivative thereof used in the above embodimentsof the process are recovered as described above and are preferablyrecycled in the process.

The novel Compound of formula (I) can be prepared according to thedifferent embodiments. For example starting from Compound (IV) asdetailed below, or other synthetic pathways disclosed herein. Althoughin the process for the preparation of Iopamidol (II) Compound (I) is notnecessarily isolated, it can be isolated, for example after reactionwith Compound (IV), as shown in the above Scheme 3 for characterizationpurposes, i.e. by ¹H-NMR. Isolation of Compound (I) can be doneaccording to conventional work-up methods, well known in the art, suchas for example, extraction, precipitation, chromatographic separation.One exemplary way to characterize the Compound (I) is dissolving it in asuitable solvent, for example dimethylacetamide, adding a precipitationsolvent, for example toluene and isolating the formed precipitate.Conveniently, the precipitate can be redissolved, for example heatingthe precipitation solution, and subsequent cooling. The obtained whitesolid is isolated, for example by filtration. The analyticalcharacterization can be done according to well-known methods, forexample elementary analysis, melting point, spectroscopy (such as NMR,IR) as better detailed in the Experimental Part.

In another aspect of the present invention, Iopamidol (II) is preparedby starting from the above Compound of formula (IV).

This Compound is a well-known intermediate, as it is its preparation, inthe prior art syntheses of Iopamidol (II), see for example WO0244125 andthe references cited therein.

According to the present invention, this Compound (IV) is treated withboric acid or a derivative thereof to provide the Compound of formula(I), as disclosed above.

Boric acid and its derivatives used in the present invention arewell-known compounds which are commercially available or can be preparedaccording to literature methods. For example, boric acid esters B(OR₂)₃,wherein R₂ is as above defined, boronic acids R₃—B(OH)₂, and boroxine offormula (III)

wherein R₃ has the same meaning and preferred embodiments as abovedefined, are described together with their preparation in the generalliterature, such as for example Ullmann's Encyclopedia of IndustrialChemistry, VCH, last edition; Dennis G. Hall (ed.) Boronic Acids, WileyVCH, last ed.; March's Advanced Organic Chemistry, Wiley, last ed.; KirkOthmer Encyclopedia of Chemical Technology, Wiley, last ed.; LawrenceBarton et al. (eds.) Boron Compounds, Springer Verlag, 1977.

Just for sake of exemplification, boric acid esters are preparedaccording to the general reaction:

wherein R₂ is as above defined.

In one embodiment of the present invention, the Compound (IV) is treatedwith boric acid and an R₂OH alcohol in a reaction medium. The reactionmedium is a solvent compatible with reaction conditions, reactants andfinal product. Conveniently, the reaction medium is the same organicsolvent used in the reaction from Compound (I) to Iopamidol (II) (stepa) (see Scheme 2). In a preferred embodiment, N,N-dimethylacetamide isthe solvent. The reaction is carried out at a temperature comprised from60° C. to 100° C. or higher, for a time sufficient to completion. Checkof completion of reaction, i.e. until the water content is at minimum orvery low, for example<0.5%, is done by conventional methods, for exampleby ¹H-NMR or by water content determination in the reaction mix, i.e. bythe Karl Fischer titration. The obtained Compound (I) can be isolated ordirectly treated with the chiral acylating agent(S)-2-(acetyloxy)propanoyl chloride in the same reaction solvent, thusachieving a “one-pot” process. The person skilled in the art knows themeaning of the term “one-pot” process and no further explanations arenecessary.

In another embodiment of the present invention, the Compound (IV) isdirectly treated with a boric acid ester B(OR₂)₃ in a reaction medium.The reaction can be carried out as for the above embodiment of boricacid and alcohol. Compound (I) can be either isolated for subsequentreaction or used in “one-pot” process.

Preferred borates are selected from the group consisting of t-butyl-,n-propyl and ethyl borate. Esters with different alkyl groups can alsobe used. The reaction can be carried out as for the above embodiment ofboric acid and alcohol. Compound (I) can be either isolated forsubsequent reaction or used in “one-pot” process.

In another embodiment of the present invention, the Compound (IV) istreated with a boronic acid anhydride, or boroxine of formula (III)above. Preferred boroxines are tri(phenyl)boroxine andtri(methyl)boroxine. The reaction can be carried out as for the aboveembodiment of boronic acid. Compound (I) can be either isolated forsubsequent reaction or used in “one-pot” process.

In a preferred embodiment, the reaction between the Compound (IV) andthe boric acid or its derivative, is carried out for a certain time andbefore shifting to the next step of N-acylation to Iopamidol (II), it isadvisable to remove part of the solvent, for example by distillation,even better by vacuum-distillation, in order to control water content,preferably until the water content is at minimum or at least very low,for example<0.5% (determined by Karl Fischer titration).

Of note the diol protection approach by the boron derivatives usedaccording to the present invention can be used also for the preparationof other iodinated X-ray contrast agents, beside Iopamidol such as forexample Iomeprol, Iodixanol, Ioversol, Iohexol, Iopromide, etc.

These latter compounds are well known in the art and, as a commonstructural feature in their molecules, they all bear carboxamido groupswherein the amino moiety correspond to 1-amino-2,3-propanediol, alsoknown as isoserinol.

Therefore, the preparation of the corresponding diol boron protectedderivatives, analogue of the aforementioned compound of Formula (I), maybe schematically represented as follows:

From the above, it should be clear to the skilled person that thepreparation of these latter derivatives wherein R has any of theaforementioned meanings may be carried out as presently reported, forthe preparation of the corresponding compound of Formula (I).

Likewise, the functionalization of the diol boron protected derivative,for instance comprising the proper acylation at the amino group on thebenzene ring, optionally followed by further alkylation at the nitrogenatom, as the case may be, with subsequent cleavage of the boronprotecting group, may then lead to any of the aforementioned contrastagents.

The synthetic schemes for the preparation of these compounds can beexemplified as follows:

The operative conditions to be employed for the preparation of thesecontrast agents essentially correspond to those reported for thepreparation of Iopamidol according to the present invention, even ifproper modifications may be needed for the preparation of any specificcontrast agent, for instance following the synthetic scheme for each ofthem, as widely reported in the literature.

In another aspect, the present invention provides a process for thepreparation of Iopamidol (II) as shown in the above Scheme 4.5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethy)ethyl]-1,3-benzenedicarboxamide(Compound (V)) is a well-known compound and one of its preparations isdisclosed for example in WO0244125. According to the present invention,this Compound is subjected to iodination of the benzene ring with amethod known in the art, for example as disclosed in the same WO0244125and references cited therein, to obtain5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethy)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide(Compound (IV)).

In another aspect, the present invention provides a process for thepreparation of Iopamidol (II) as shown in the above Scheme 5. Startingfrom 5-nitro-1,3-benzenedicarboxylic acid (5-nitroisophthalic acid or5-NIPA),5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethy)ethyl]-1,3-benzenedicarboxamide(V) is prepared, for example as disclosed in WO0244125 and WO0029372.

According to the present invention, this Compound (V) is subjected toiodination of the benzene ring as above mentioned to obtain5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethy)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide(Compound (IV)).

Compound (IV) is then processed according to the present invention toIopamidol (II) through the intermediate (I).

Advantageously, a “one-pot” process can be performed.

The preferred synthetic pathway to Compound (V) is described in theScheme 6 below, shown for one exemplary embodiment:

The scheme 6 represents the synthetic pathway to Iopamidol (II) from5-NIPA according to an exemplary embodiment.

The first part of the synthesis, from NIPA to Compound (V), is a“one-pot” synthesis, without intermediate isolation. It consists ofthree steps (esterification, hydrogenation, amidation), carried out in aconvenient solvent, for example n-butanol in case a n-butyl ester ispreferred. The esterification is performed in presence of a well-knownesterification catalyst, for example an acid catalyst such aspara-toluensulfonic acid, methansulfonic acid, sulfuric acid, preferablymethanesulfonic acid. Subsequently, the hydrogenation is carried out asknown by the skilled man, for example as described in EP1337505 andpreferably by catalytic hydrogenation in presence of 5% Pd/C or otherequivalent catalyst. In this case, after catalyst removal, the mixtureis concentrated for the next amidation step, which is carried outessentially by two alternative methods:

-   -   Amidation neat, without solvent and with a consistent excess of        serinol, that is recovered by an anionic resin and recycled in        the reaction. Compound (V) is not isolated, but directly        transferred to a new reactor vessel for the iodination step.    -   Amidation in the presence of an organic solvent and a co-solvent        as described in EP1337505 preferably in methanol, in presence of        a basic catalyst. During the reaction a precipitation occurs and        the obtained Compound (V) is filtered off. The solid is directly        redissolved in water and transferred to the next reactor vessel        for the iodination step.

A preferred embodiment is represented by the amidation in the presenceof an organic solvent and a co-solvent.

The iodination reaction is performed on an aqueous solution containingCompound (V), synthesized following one of the two approaches mentionedabove. The iodination procedure is done according to well-known methods,see above for related references, to give the intermediate (IV). Thenthe process proceeds as disclosed above according to steps a)-c).

According to a further embodiment, the invention refers to a process forthe recovery of boronic acids from a reaction mixture where these areused as diol protecting groups. This allows their re-use for the samepurpose in a new synthesis. Even though this recovery and recycling ispreferably carried out in the process for the preparation of Iopamidolaccording to the present invention and as described above, the recoveryrepresents a more general embodiment for boronic acids recycling,because it provides quantitative yields (usually >90%, preferably >95%and more preferably at least 99%) of these generally expensive reagents,thus representing a great economic advantage for large scaleindustrialization.

An even greater advantage can be foreseen when this process is carriedout in a continuous mode and in industrial processes where recovery andrecycling can be optimized.

According to this embodiment, the aqueous reaction mixture obtainedafter hydrolysis of the diol protective groups, which comprises theboronic acid used for diol protection or in which a boronic acid isformed after hydrolysis (for example when a boroxine of Formula III isused for diol protection) and which optionally comprises a polar solventsuch as: N,N-dimethylformamide, N,N-dimethylacetamide (DMAC),N,N-diethylacetamide, N,N-dimethylpropionamide, N-methylpyrrolidone,N-ethylpyrrolidone, tetramethylurea, N,N′-dimethylethyleneurea (DMEU),N,N′-dimethylpropyleneurea (DMPU) is added with an organicwater-immiscible solvent.

The organic water-immiscible solvent is selected among:4-methyl-2-pentanone (MIBK), 3-pentanone, 2-pentanone, dibutyl ether,2-methyl-tetrahydrofurane, ciclopentylmethyl ether, methyl isopropylketone, methyl isopentyl ketone ethyl acetate, butyl acetate, pentylacetate, isopentyl acetate, isopropyl acetate.

A preferred ratio between the boronic acid and the water-immisciblesolvent (the boronic acid extraction solvent) is comprised from1:10-1:20 (w/w) more preferably comprised from 1:13-1:16 and even morepreferably about 1:15.

The boronic acid used as the boron-containing diol protective group,recovered according to this embodiment, is preferably phenylboronic,p-tolyl boronic or butyl boronic acid, or when phenylboroxine ormethylboroxine are used for diol protection, phenylboronic acid ormethyl boronic acid can be recovered upon hydrolysis.

The water immiscible organic solvent can be further re-extracted with analiquot of an aqueous solution with a pH comprised from 0-7, orpreferably close to neutrality at a pH comprised from 6 to 7 when therecovery is carried out after hydrolysis of Compound I and according tothe present invention to improve the selectivity of boronic acidrecovery.

Partitioning of the boronic acid into the organic phase for its recoverycan be achieved either in batch or in a continuous mode, by optimizationmethods known to the skilled man.

The following examples further illustrate the invention in more details.

EXAMPLE 1 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boronic Acid

With reference to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(IV) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (363 g; 2.98 mol)were mixed in N,N-dimethylacetamide (4 kg). The suspension was stirredand heated at 90-95° C. The solution obtained was heated at 90-95° C.for 1 h then N,N-dimethylacetamide (about 3 kg) was distilled undervacuum and brought to a water content lower than 0.5%, assessed by KarlFischer titration. At this point the formation of intermediate (I) wascomplete (assessed by ¹H-NMR). The residue was cooled to 30-35° C. and,under nitrogen atmosphere, (S)-2-(acetyloxy)propanoyl chloride (380 g;2.52 mol) was slowly added. The mixture was stirred for 18 h at roomtemperature and under nitrogen atmosphere then water was added to obtaina diluted solution, suitable for the chromatographic purification. After1 h of stirring the solution was loaded onto a column of Amberlite®IRA743 (17 L) (Dow Chemical Company) and eluted with water (3 bedvolumes). The solution was loaded onto a column of Relite® 3ASFB(anionic resin; 4 L) and the eluate was discharged. The Relite 3ASFBcolumn was then sequentially eluted with 2 bed volumes of an aqueousacidic solution (diluted hydrochloric acid), and washed with 3-4 BV (bedvolumes) of water, quantitatively recovering the substrate. The obtainedsolution was neutralized to pH 7, concentrated by vacuum distillationover 2 hours. The solution was loaded onto a column of Amberlite® XAD1600 (3.6 L) (Dow Chemical Company) and eluted with 4 BV of highlydiluted sodium hydroxide solution. The solution was loaded onto two ionexchange resin columns (cationic Dowex® C350, 4.7 L; anionic Relite®MG1/P, 2 L, Dow Chemical Company). The eluate was concentrated and thesolid residue was crystallized from 2-butanol to afford Iopamidol (II)(904 g; 1.16 mol) as a pure white solid with a yield of 82%.

The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure.

Phenylboronic acid was recovered with a >90% yield.

An identical procedure was employed with n-butylboronic acid (X=n-Bu)and Iopamidol (II) was recovered with an 80% yield.

EXAMPLE 2 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boronic Acid

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(IV) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (363 g; 2.98 mol)were mixed in N,N-dimethylacetamide (4 kg). The suspension was stirredand heated at 90-95° C. The solution obtained was heated at 90-95° C.for 1 h then N,N-dimethylacetamide (about 3 kg) was distilled undervacuum. The residue should have water content lower than 0.5%, assessedby Karl Fischer titration. At this point the formation of intermediate(I) was complete, as determined by ¹H-NMR on an aliquot of the reactionmixture, dried and the residue treated as described below. The residuewas cooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (384 g; 2.55 mol) was slowly added.The mixture was stirred for 18 h at room temperature and under nitrogenatmosphere then water (9 kg) was added. After 1 h of stirring thesolution was loaded onto a column of Relite MG1/P (2.2 L) and elutedwith water (15 L). The solution was extracted with 4-methyl-2-pentanone(3×4 L) and the aqueous phase was loaded onto a Relite 3ASFB column forthe hydrolysis, sequentially eluted with 2 bed volumes of an aqueousacidic solution (diluted hydrochloric acid), and washed with 3-4 bedvolumes of water, quantitatively recovering the substrate. The obtainedsolution was neutralized to pH 7, concentrated by vacuum distillationover 2 hours. The solution was loaded onto a column of Amberlite® XAD1600 (3.6 L) and eluted with 4 BV of highly diluted sodium hydroxidesolution. The solution was loaded onto two ion exchange resin columns(cationic Dowex® C350, 4.7 L; anionic Relite® MG1/P, 2 L). The eluatewas concentrated and the solid residue was crystallized from 2-butanolto afford Iopamidol (II) (959 g; 1.23 mol) as a pure white solid, with ayield of 87%. The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure. Phenylboronic acid was recovered with a >95% yield.The solvent was distilled off and a concentrated solution is directlyreemployed in the synthesis.

Phenylboronic acid was also extracted with 3-pentanone with comparableresults.

Procedure for the Isolation of Compound (I):

The protected intermediate (12.4 g) was re-dissolved indimethylacetamide (10 g) and toluene (100 mL) was added to form aprecipitate. The solution was heated at 60° C. over 30 minutes and theprecipitate was redissolved; the solution was cooled to 5° C. over 2 hand the obtained solid was filtered off, affording a white solid. Theanalytical characterization is in agreement with the proposed structure.

Melting point=180-185° C.

¹H-NMR (DMSO-d₆) (ppm): 4.07 (dd, 1H, 7), 4.31 (dd, 1H, 7), 4.38 (m, 1H,6), 7.35 (t, 1H, 10), 7.43 (t, 1H, 11), 7.70 (d, 1H, 9), 9.12 (d, 1H,CONH).

¹³C-NMR (DMSO-d₆) (ppm): 45.35 (C6), 64.05 (C7), 74.45 (C4), 80.30 (C2),127,94 (C10), 131.06 (C11), 133.00 (C8), 134.05 (C9), 147.88 (C1),148.82 (C3), 170.20 (C5).

EXAMPLE 3 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boronic Acid

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (360 g; 2.95 mol)were mixed in N,N-dimethylacetamide (0.76 kg) and methyl isobutyl ketone(MIBK) (3.24 kg). The suspension was stirred and heated at 90-95° C.,then MIBK/water mixture (2.8 kg) was distilled under vacuum and broughtto a water content lower than 0.5%, assessed by Karl Fischer titration,obtaining a clear yellow solution. At this point the formation ofintermediate (I) was complete (assessed by ¹H-NMR). The residue wascooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at 30-35° C. and under nitrogenatmosphere then diluted NaOH solution was added to neutral pH. Anotherportion of methyl isobutyl ketone (4-5 kg) was added to the biphasicmixture and phenylboronic acid was extracted. The aqueous phase wasloaded onto two ion exchange resin columns (a cationic resin, Dowex®C350, 2 L; an anionic resin Relite® MG1/P, 2.6 L). The columns wereeluted with 2 BV of water. The solution obtained was loaded onto Relite3ASFB column for the hydrolysis: Iopamidol (II) was recovered by elutionwith 2 BV of an aqueous acidic solution (diluted hydrochloric acid), andwashed with 3-4 bed volumes of water. The obtained solution wasneutralized to pH 7, concentrated by vacuum distillation over 2 hours.The solution was loaded onto a column of Amberlite® XAD 1600 (3.6 L) andeluted with 4 BV of highly diluted sodium hydroxide solution. Thesolution was loaded onto two ion exchange resin columns (cationic Dowex®C350, 4.7 L; anionic Relite® MG1/P, 2 L). The eluate was concentratedand the solid residue was crystallized from 2-butanol to affordIopamidol (II) (992 g; 1.28 mol) as a white solid. Yield 90%.

PBA was recovered with a yield of 95%.

Example 4 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boronic Acid

The synthesis was carried out essentially as described in Example 3.Briefly, and referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (360 g; 2.95 mol)were mixed in N,N-dimethylacetamide (0.76 kg) and methyl isobutyl ketone(MIBK) (3.24 kg). The suspension was stirred and heated at 90-95° C.,then MIBK/water mixture (2.8 kg) was distilled under vacuum and broughtto a water content lower than 0.5%, assessed by Karl Fischer titration,obtaining a clear yellow solution. At this point the formation ofintermediate (I) was complete as assessed by ¹H-NMR. The residue wascooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at 30-35° C. and under nitrogenatmosphere, then diluted NaOH (9 kg). solution was added to neutral pH.PBA was extracted with three portion of methyl isobutyl ketone (3×3.2kg).The aqueous phase was loaded onto two ion exchange resin columns (acationic resin, Dowex® C350, 2 L; an anionic resin Relite® MG1/P, 2.6L). The columns were eluted with water. The solution obtained was loadedonto Relite 3ASFB column for the hydrolysis: Iopamidol (II) wasrecovered by elution with an aqueous acidic solution (dilutedhydrochloric acid), and washed with water. The obtained solution wasloaded onto a column of Relite® MG1/P (1.8 L), Amberlite® XAD 1600 (3.6L) and cationic Dowex® C350 (0.2 L), and eluted with 4 BV of highlydiluted sodium hydroxide solution. The eluate was concentrated and thesolid residue was crystallized from 2-butanol to afford Iopamidol (II)(1003 g; 1.29 mol) as a white solid. Yield 91%. PBA was recovered with ayield of 95%.

EXAMPLE 5 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Recycled Phenyl Boronic Acid (PBA)

It has been tested whether the recovered phenyl boronic acid could bere-used by direct addition to the reaction mixture.

Referring to Scheme 3, the organic phase (MIBK containing phenyl boronicacid), obtained from phenylboronic acid extraction and recovered fromthe reaction mixture obtained in example 4, was used to perform asynthesis of a new batch of Iopamidol. DMAC (0.6 kg) was first added tothe organic mixture and the solution was distilled under vacuum at <40°C. concentrating the PBA, to reach a suitable concentration.Subsequently the organic solution, containing 95% of the requiredrecovered phenyl boronic acid, was mixed with-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and fresh phenylboronic acid (X=Ph) (18 g; 0.15mol), corresponding to about 5% of the total amount required, was added.The suspension was stirred and heated at 90-95° C., and the reaction wascontinued as described in Example 4, affording Iopamidol yieldscomparable to that obtained with solid (fresh) PBA.

EXAMPLE 6 Preparation of Iopamidol (II) Starting from Compound (IV) withPhenylboronic Acid (PBA) in DMAC and a Co-Solvent. Recovery of PBA

The synthesis was carried out substantially as described in Example 4,but using reduced volumes. Briefly:5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (360 g; 2.95 mol)were mixed in N,N-dimethylacetamide (0.76 kg) and methyl isobutyl ketone(MIBK) (3.24 kg). The suspension was stirred and heated at 90-95° C.,then MIBK/water mixture (2.8 kg) was distilled under vacuum and broughtto a water content lower than 0.5%, assessed by Karl Fischer titration,obtaining a clear yellow solution. At this point the formation ofintermediate (I) was complete as assessed by 1H-NMR. The residue wascooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at 30-35° C. and under nitrogenatmosphere, then NaOH (2.7 kg) was added to neutral pH. Another portionof methyl isobutyl ketone (2 kg) was added to the biphasic mixture andphenylboronic acid was extracted. The organic phase was washed withwater (0.9 kg) and the aqueous phases were collected and extracted withtwo other portions of MIBK (2 kg). Less than 0.8% of Acetyl-Iopamidolpassed into the organic phase. The aqueous phase was loaded into two ionresin columns and the work up was continued as described above.

The organic phase (MIBK containing phenyl boronic acid), obtained fromphenylboronic acid extraction and recovered from the reaction mixture,was used to perform a synthesis of a new batch of Iopamidol, essentiallyas described in Example 5. Briefly, DMAC (0.6 kg) was first added to theorganic mixture and the solution was distilled under vacuum at <40° C.removing 2-2.3 kg of MIBK in order to have a final amount of 3.65 Kg ofMIBK. Subsequently the organic solution, containing 95% of the requiredrecovered phenyl boronic acid, was mixed with-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and fresh phenylboronic acid (X=Ph) (18 g; 0.15mol), corresponding to about 5% of the total amount required, was added.The suspension was stirred and heated at 90-95° C., and the reaction wascontinued as previously described, to Iopamidol.

EXAMPLE 7 Preparation of Iopamidol (II) Starting from Compound (IV) withPhenylboronic Acid (PBA) in DMAC and a Co-Solvent. Recovery of PBA with2-Pentanone

The process was carried out substantially as described in Example 4using 2-pentanone instead of MIBK. In brief:5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and phenylboronic acid (X=Ph) (360 g; 2.95 mol)were mixed in N,N-dimethylacetamide (0.76 kg) and 2-pentanone (3.24 kg).The suspension was stirred and heated at 90-95° C., then2-pentanone/water mixture (2.8 kg) was distilled under light vacuum andbrought to a water content lower than 0.5%, assessed by Karl Fischertitration, obtaining a clear yellow solution. At this point theformation of intermediate (I) was complete as assessed by 1H-NMR. Theresidue was cooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at 30-35° C. and under nitrogenatmosphere, then NaOH solution (4.4 kg) was added to neutral pH. Anotherportion of 2-pentanone (2.4 kg) was added to the biphasic mixture andphenylboronic acid was extracted. The extraction was repeated 2 moretimes with 2-pentanone (1.6 kg×2). A quantitative recovery of PBA wasachieved but ca. 4% of Acetyl-Iopamidol was found into the organicphase.

The procedure was repeated by washing the organic phase (2-pentanone)with water thus recovering more product and affording an equivalent PBArecovery.

EXAMPLE 8 Recovery of PBA by Using Diluted NaOH Solution and HigherSolvent Volumes

The process was carried out substantially as described in Examples 6 and7 but using higher volumes of a more diluted NaOH solution. In thiscase, the aqueous phase was re-extracted with about twice the volume ofsolvent to achieve the same recovery of Acetyl-Iopamidol and PBA.

A similar workout was carried out with 3-pentanone, 2-pentanone, methylisopropyl ketone, methyl-isopenthyl ketone and cyclopentyl methyl ether,that afforded comparable Iopamidol synthetic yields, as well as bothIopamidol and PBA recovery yields.

EXAMPLE 9 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing p-Tolylboronic Acid

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and p-tolylboronic acid (405 g; 2.98 mol) weremixed in N,N-dimethylacetamide (0.75 kg) and methyl isobutyl ketone(MIBK) (3.25 kg). The suspension was stirred and heated at 90-95° C.,then MIBK/water mixture (2.8 kg) was distilled under vacuum and broughtto a water content lower than 0.5%, assessed by Karl Fischer titration,obtaining a clear yellow solution. At this point the formation ofintermediate (I) was complete as assessed by 1H-NMR. The residue wascooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at 30-35° C. and under nitrogenatmosphere, then diluted NaOH solution was added to neutral pH. Anotherportion of methyl isobutyl ketone (4 kg) was added to the biphasicmixture and p-tolylboronic acid was extracted. The aqueous phase wasloaded onto two ion exchange resin columns (a cationic resin, Dowex®C350, 2 L; an anionic resin Relite® MG1/P, 2.6 L) and the work-up wascontinued as described in Example 4 to afford Iopamidol (II) (992 g;1.28 mol) as a white solid. Yield 90%

EXAMPLE 10 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing Butylboronic Acid

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (1 kg; 1.42 mol) and butylboronic acid (303.6 g; 2.98 mol) weremixed in N,N-dimethylacetamide (4.0 kg). The suspension was stirred andheated at 90-95° C., then DMA/water mixture (2.8 kg) was distilled undervacuum and brought to a water content lower than 0.5%, assessed by KarlFischer titration, obtaining a clear yellow solution. At this point theformation of intermediate (I) was complete as assessed by 1H-NMR. Theresidue was cooled to 25° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (380 g; 2.52 mol) was slowly added.The mixture was stirred for 18 h at RT and under nitrogen atmosphere,then diluted NaOH solution was added to neutral pH. A portion of methylisobutyl ketone (5 kg) was added to the biphasic mixture andbutylboronic acid was extracted. The aqueous phase was loaded onto twoion exchange resin columns (a cationic resin, Dowex® C350, 2 L; ananionic resin Relite® MG1/P, 2.6 L) and the work-up was continued asdescribed in Example 4 to afford Iopamidol (II) (992 g; 1.28 mol) as awhite solid. Yield 90%.

EXAMPLE 11 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boroxine

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(V) (255 g; 0.362 mol) and triphenylboroxine (Compound (III), R₃ ₌Ph)(82.3 g; 0.264 mol) were mixed in N,N-dimethylacetamide (1 kg). Thesuspension was stirred and heated at 90-95° C. The solution obtained washeated at 90-95° C. for 1 h then N,N-dimethylacetamide (about 700 g) wasdistilled under vacuum. The residue should have water content lower than0.5%, assessed by Karl Fischer titration. At this point the formation ofintermediate (I) was complete (assessed by ¹H-NMR). The residue wascooled to 30-35° C. and, under nitrogen atmosphere,(S)-2-(acetyloxy)propanoyl chloride (98 g; 0.651 mol) was slowly added.The mixture was stirred for 18 h at room temperature and under nitrogenatmosphere then water (190 g) was added. After 1 h of stirring thesolution was purified by elution on a series of columns as described inExample 4 to afford Iopamidol (II) (219 g; 0.282 mol) as a white solid.

Yield: 78%. The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure. An identical procedure was employed withtrimethylboroxine (III) (R₃ ₌Me); Iopamidol (II) yield was 75%.

EXAMPLE 12 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boric Acid Ester

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(IV) (200 g; 0.284 mol) in N,N-dimethylacetamide (800 g) was heated at60° C. obtaining a solution then tri-n-butyl borate (X=OR₂, R₂=n-Bu)(137.2 g; 0.596 mol) was added. The solution was stirred and heated at105° C. for 2 h then N,N-dimethylacetamide and n-butanol were distilledunder vacuum collecting about 730 g of distillate. MoreN,N-dimethylacetamide (95 g) was added to the reaction mixture anddistilled under vacuum. At this point the formation of intermediate (I)was complete (assessed by ¹H-NMR). The residue was cooled to roomtemperature and, under nitrogen atmosphere, (S)-2-(acetyloxy)propanoylchloride (85.5 g; 0.568 mol) was slowly added. The mixture was stirredfor 18 h at room temperature and under nitrogen atmosphere then water(1.5 kg) was added, deprotecting the hydroxyl groups and obtaining adiluted solution suitable for the chromatographic purification. After 1h of stirring the solution was loaded onto a column of XAD® 1600 (4 L),the resin was washed with water (3 BV) and the eluate containing boricacid, N,N-dimethylacetamide and butanol was loaded onto a column ofIRA743 (4.1 L) for DMAC, butanol and boric acid recovery. AcetylIopamidol was eluted from XAD 1600 with NaOH (0.20% w/w; 5 BV),concentrated under vacuum to a final volume of 2 L and hydrolyzed inbatch with NaOH at pH=12 at 35° C. over 20-24 hours. The solution wasloaded onto two ion exchange resins (a cationic Amberjet® 1200, 0.9 L;an anionic Relite® MG1, 0.8 L). The eluate was concentrated and thesolid residue was crystallized from 2-butanol to afford Iopamidol (II)(159 g; 0.205 mol) as a white solid.

Yield: 72%. The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

An identical procedure was employed with triethyl borate andtri-n-propyl borate.

EXAMPLE 13 Preparation of Iopamidol (II) Starting from Compound (IV) andUsing a Boric Acid and Alcohol

Referring to Scheme 3,5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenecarboxamide(IV) (200 g; 0.284 mol), n-BuOH (600 g, 8.10 mol) and boric acid (36,8g, 0,60 mol) were suspended in N,N-dimethylacetamide (720 g) and heatedat 60° C., obtaining an homogeneous solution. The solution was stirredand heated at 90° C. for 1 h then N,N-dimethylacetamide and n-butanolwere distilled under vacuum over 4 h, collecting about 1.1 kg ofdistillate. At this point the formation of intermediate (I) was complete(assessed by ¹H-NMR). The residue was cooled to room temperature and,under nitrogen atmosphere, (S)-2-(acetyloxy)propanoyl chloride (85.28 g;0.57mol) was slowly added. The mixture was stirred over 18 h at roomtemperature under nitrogen atmosphere, then water (1.5 kg) was added.After 1 h of stirring the solution was loaded onto a column of XAD® 1600(4 L), the resin was washed with water (3 BV) and the eluate containingboric acid, DMAC and n-BuOH was loaded onto a column of IRA743 (4.1 L)for DMAC, n-BuOH and boric acid recovery. Acetyl Iopamidol was elutedfrom XAD 1600 with NaOH (0.20% w/w; 5 bed volumes), concentrated undervacuum to a final volume of 2 L and hydrolyzed in batch with NaOH atpH=12 and at 35° C. The solution was loaded onto two ion exchange resins(a cationic Amberjet® 1200, 0.9 L; an anionic Relite® MG1, 0.8 L). Theeluate was concentrated and the solid residue was crystallized from2-butanol to afford Iopamidol (II) (170 g; 0.218 mol) as a white solid.Yield: 77%.

EXAMPLE 14 Procedure: One Pot Synthesis Starting from 5-NitroisophthalicAcid to Compound (V)

Referring to Scheme 6, 5-nitro isophthalic acid (NIPA; 100 g; 0.47 mol)was dissolved in butanol (600 g), in the presence of a catalytic amountof monohydrated p-toluenesulphonic acid (9.01 g; 0.047 mol). The mixturewas heated at 125° C. and the water was azeotropically removed bydistillation. The intermediate (VI) was obtained with a quantitativeconversion (>98%). The homogeneous solution was hydrogenated withoutisolation in presence of 5% Pd/C (3.0 g) as a catalyst. The obtainedsuspension was maintained under mechanical stirring and purged withnitrogen washings, at the end of which the hydrogenation reaction wascarried out at a temperature comprised between 50 and 70° C. Thereaction was complete in 4-8 hours (132.76 g; 0.453 mol). A nitrogenflow was passed through the reaction vessel to wash out any hydrogengas, the catalyst was filtered off and the obtained solution transferredto a new reactor.

Concerning the amidation, the reaction was carried out by twoalternatives methods.

i) Amidation employing methanol as a co-solvent:

Serinol in slight excess (94.84 g; 1.04 mol) was loaded to thehydrogenated mixture, containing 132.76 g of (VII). The solution wasconcentrated, removing the water generated in the previous step and mostof the butanol.

The mixture was cooled, methanol (524 g) was added and the temperaturewas increased to 55-60° C. A solution of sodium methylate (21.19 g;0.118 mol) in methanol was added dropwise and kept to this temperatureuntil complete conversion (7-10 hours). The mixture was cooled to 15° C.and kept for 3 h, and then the solid was filtered off, affording a whitesolid (V), that was washed with methanol. The solid obtained wasdirectly redissolved in water and transferred to a reactor for the nextiodination reaction. Yield based on a dried solid=95%

ii) Neat amidation, with an excess of serinol:

The hydrogenated mixture, containing (VII) (132.76 g; 0.45 mol) wascooled to room temperature and an excess of serinol (247.40 g; 2.72 mol)was added. The solution was concentrated, azeotropically removing themixture water/butanol at 100° C. under vacuum. The mixture was heated at125° C. over a period of 4-6 hours, then cooled at 70-80° C. Water(929.3 g) was loaded into the reactor. The diluted solution thusobtained was loaded onto a series of two columns, the first one was aweak acidic resin (carboxylic, 700 mL) to selectively recover andrecycle serinol, the second one was an anionic resin (tertiary amine, 50mL) to purify the (V) solution.

Procedure for Iodination: with (V) coming from co-solvent procedure:

ia) The wet solid (735 g; 2.05 mol) was redissolved in water (7 L), theresidual methanol was distilled off, heating at 70-75° C., then thesolution was heated at 70-90° C. and sulfuric acid (106 g; 1.03 mol) wasloaded. ICI (1919 g; 6.65 mol) was added dropwise over 1.5 h. (IV)started to precipitate and the suspension was heated over 6-8 h. Thesuspension was cooled to room temperature and the precipitate filteredoff, affording a white solid. Yield=92%

iia) Iodination with (V) coming from neat procedure:

The solution coming from the amidation was concentrated, heated at70-90° C. and sulfuric acid was loaded. The procedure was as reportedabove.

The synthesis of Iopamidol (II) was then carried out according to scheme3 or to any one of the preceding Examples.

1. A method of X-rays contrast imaging a subject comprising administering Iopamidol to a subject and obtaining an X-rays contrast image of the subject, wherein Iopamidol is prepared according to a process comprising the following reaction:

wherein X is OR₂ or R₃, and wherein R₂ and R₃ are a C₁-C₆ linear or branched alkyl, C₃-C₆ cycloalkyl, C₆ aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl; and comprising the following steps: a) reacting the Compound (I) with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the N-(S)-2-(acetyloxy)propanoyl derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7 by adding water or a diluted alkaline solution, freeing the hydroxyls from the boron-containing protective groups, obtaining the acetyloxy derivative of Compound (II) and optional recovery of the boron derivative; c) alkaline hydrolysis of the acetyloxy derivative of Compound (II) restoring the (S)-2-(hydroxy)propanoyl group to obtain Iopamidol (II).
 2. The method according to claim 1, wherein X is OR₂.
 3. The method according to claim 1, wherein X is R₃.
 4. The method according to claim 1, wherein said Compound of formula (I) is prepared starting from the Compound of formula (IV), according to the following reaction:

wherein X is OR₂ or R₃, and wherein R₂ and R₃ are a C₁-C₆ linear or branched alkyl, C₃-C₆ cycloalkyl, C₆ aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl; and comprising: reacting the Compound of formula (IV) with one of a boric acid in an R₂OH alcohol or a borate ester B(OR₂)₃, wherein R₂ is as above defined, to provide the Compound of formula (I), wherein X is OR₂; or reacting the Compound of formula (IV) with one of a boronic acid R₃—B(OH)₂, or a boroxine of formula (III):

to provide the Compound of formula (I), wherein X is R₃.
 5. The method according to claim 4, wherein the boronic acid is selected from the group consisting of: phenylboronic acid, tolylboronic acid and butylboronic acid or the boroxine (III) is selected from the group consisting of tri-phenylboroxine and tri-methylboroxine.
 6. The method according to claim 4, wherein said Compound of formula (IV) is prepared submitting to iodination the following Compound (V):


7. The method according to claim 6, wherein said Compound (V) is prepared according to the following reaction scheme:

wherein: i) 5-nitroisophthalic acid is treated with an R₁OH alcohol, wherein R₁ is a linear or branched C₁-C₄alkyl, to provide the corresponding diester; ii) the 5-nitro group is reduced to the corresponding 5-amino group to provide the Compound (VII); iii) the diester is reacted with 2-amino-1,3-propandiol to provide the Compound (V).
 8. The method according to claim 1, further comprising the purification and isolation of Iopamidol (II).
 9. The method according to claim 8, wherein said purification is to pharmaceutical grade. 